Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

A Nicolas, KP Kenna, AE Renton, N Ticozzi, F Faghri, R Chia, JA Dominov, BJ Kenna, MA Nalls, P Keagle, AM Rivera, W van Rheenen, NA Murphy, JJFA van Vugt, JT Geiger, RA Van der Spek, HA Pliner, Shankaracharya [No Value], BN Smith, G MarangiSD Topp, Y Abramzon, AS Gkazi, JD Eicher, A Kenna, ITALSGEN Consortium, G Mora, A Calvo, L Mazzini, N Riva, J Mandrioli, C Caponnetto, S Battistini, P Volanti, V La Bella, FL Conforti, G Borghero, S Messina, IL Simone, F Trojsi, F Salvi, FO Logullo, S D'Alfonso, L Corrado, M Capasso, L Ferrucci, Genomic Translation for ALS Care (GTAC) Consortium, CAM Moreno, S Kamalakaran, DB Goldstein, ALS Sequencing Consortium, AD Gitler, T Harris, RM Myers, NYGC ALS Consortium, H Phatnani, RL Musunuri, US Evani, A Abhyankar, MC Zody, Answer ALS Foundation, J Kaye, S Finkbeiner, SK Wyman, A LeNail, L Lima, E Fraenkel, CN Svendsen, LM Thompson, JE Van Eyk, JD Berry, TM Miller, SJ Kolb, M Cudkowicz, E Baxi, Clinical Research in ALS, Related Disorders for Therapeutic Development (CReATe) Consortium, M Benatar, JP Taylor, E Rampersaud, G Wu, J Wuu, SLAGEN Consortium, G Lauria, F Verde, I Fogh, C Tiloca, GP Comi, G Sorarù, C Cereda, French ALS Consortium, P Corcia, H Laaksovirta, L Myllykangas, L Jansson, M Valori, J Ealing, H Hamdalla, S Rollinson, S Pickering-Brown, RW Orrell, KC Sidle, A Malaspina, J Hardy, AB Singleton, JO Johnson, S Arepalli, PC Sapp, D McKenna-Yasek, M Polak, S Asress, S Al-Sarraj, A King, C Troakes, C Vance, J de Belleroche, F Baas, ALMA Ten Asbroek, JL Muñoz-Blanco, DG Hernandez, J Ding, JR Gibbs, SW Scholz, MK Floeter, RH Campbell, F Landi, R Bowser, SM Pulst, JM Ravits, DJL MacGowan, J Kirby, EP Pioro, R Pamphlett, J Broach, G Gerhard, TL Dunckley, CB Brady, NW Kowall, JC Troncoso, I Le Ber, K Mouzat, S Lumbroso, TD Heiman-Patterson, F Kamel, L Van Den Bosch, RH Baloh, TM Strom, T Meitinger, A Shatunov, KR Van Eijk, M de Carvalho, M Kooyman, B Middelkoop, M Moisse, RL McLaughlin, MA Van Es, M Weber, KB Boylan, M Van Blitterswijk, R Rademakers, KE Morrison, AN Basak, JS Mora, VE Drory, PJ Shaw, MR Turner, K Talbot, O Hardiman, KL Williams, JA Fifita, GA Nicholson, IP Blair, GA Rouleau, J Esteban-Pérez, A García-Redondo, A Al-Chalabi, Project MinE ALS Sequencing Consortium, E Rogaeva, L Zinman, LW Ostrow, NJ Maragakis, JD Rothstein, Z Simmons, J Cooper-Knock, A Brice, SA Goutman, EL Feldman, SB Gibson, F Taroni, A Ratti, C Gellera, P Van Damme, W Robberecht, P Fratta, M Sabatelli, C Lunetta, AC Ludolph, PM Andersen, JH Weishaupt, W Camu, JQ Trojanowski, VM Van Deerlin, Jr Brown RH, LH van den Berg, JH Veldink, MB Harms, JD Glass, DJ Stone, P Tienari, V Silani, A Chiò, CE Shaw, BJ Traynor, JE Landers

Research output: Contribution to journalArticle

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS. © 2018 Elsevier Inc.
Original languageEnglish
Pages (from-to)1268-1283.e6
JournalNeuron
Volume97
Issue number6
DOIs
Publication statusPublished - 2018

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Kinesin
Genome
Mutation
Genes
Genome-Wide Association Study
Hereditary Spastic Paraplegia
Exome
Phenotype
Neurodegenerative Diseases
Tooth
Survival

Cite this

Nicolas, A., Kenna, KP., Renton, AE., Ticozzi, N., Faghri, F., Chia, R., ... Landers, JE. (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. / Nicolas, A; Kenna, KP; Renton, AE; Ticozzi, N; Faghri, F; Chia, R; Dominov, JA; Kenna, BJ; Nalls, MA; Keagle, P; Rivera, AM; van Rheenen, W; Murphy, NA; van Vugt, JJFA; Geiger, JT; Van der Spek, RA; Pliner, HA; [No Value], Shankaracharya; Smith, BN; Marangi, G; Topp, SD; Abramzon, Y; Gkazi, AS; Eicher, JD; Kenna, A; Consortium, ITALSGEN; Mora, G; Calvo, A; Mazzini, L; Riva, N; Mandrioli, J; Caponnetto, C; Battistini, S; Volanti, P; La Bella, V; Conforti, FL; Borghero, G; Messina, S; Simone, IL; Trojsi, F; Salvi, F; Logullo, FO; D'Alfonso, S; Corrado, L; Capasso, M; Ferrucci, L; Consortium, Genomic Translation for ALS Care (GTAC); Moreno, CAM; Kamalakaran, S; Goldstein, DB; Consortium, ALS Sequencing; Gitler, AD; Harris, T; Myers, RM; Consortium, NYGC ALS; Phatnani, H; Musunuri, RL; Evani, US; Abhyankar, A; Zody, MC; Foundation, Answer ALS; Kaye, J; Finkbeiner, S; Wyman, SK; LeNail, A; Lima, L; Fraenkel, E; Svendsen, CN; Thompson, LM; Van Eyk, JE; Berry, JD; Miller, TM; Kolb, SJ; Cudkowicz, M; Baxi, E; ALS, Clinical Research in; Consortium, Related Disorders for Therapeutic Development (CReATe); Benatar, M; Taylor, JP; Rampersaud, E; Wu, G; Wuu, J; Consortium, SLAGEN; Lauria, G; Verde, F; Fogh, I; Tiloca, C; Comi, GP; Sorarù, G; Cereda, C; Consortium, French ALS; Corcia, P; Laaksovirta, H; Myllykangas, L; Jansson, L; Valori, M; Ealing, J; Hamdalla, H; Rollinson, S; Pickering-Brown, S; Orrell, RW; Sidle, KC; Malaspina, A; Hardy, J; Singleton, AB; Johnson, JO; Arepalli, S; Sapp, PC; McKenna-Yasek, D; Polak, M; Asress, S; Al-Sarraj, S; King, A; Troakes, C; Vance, C; de Belleroche, J; Baas, F; Ten Asbroek, ALMA; Muñoz-Blanco, JL; Hernandez, DG; Ding, J; Gibbs, JR; Scholz, SW; Floeter, MK; Campbell, RH; Landi, F; Bowser, R; Pulst, SM; Ravits, JM; MacGowan, DJL; Kirby, J; Pioro, EP; Pamphlett, R; Broach, J; Gerhard, G; Dunckley, TL; Brady, CB; Kowall, NW; Troncoso, JC; Le Ber, I; Mouzat, K; Lumbroso, S; Heiman-Patterson, TD; Kamel, F; Van Den Bosch, L; Baloh, RH; Strom, TM; Meitinger, T; Shatunov, A; Van Eijk, KR; de Carvalho, M; Kooyman, M; Middelkoop, B; Moisse, M; McLaughlin, RL; Van Es, MA; Weber, M; Boylan, KB; Van Blitterswijk, M; Rademakers, R; Morrison, KE; Basak, AN; Mora, JS; Drory, VE; Shaw, PJ; Turner, MR; Talbot, K; Hardiman, O; Williams, KL; Fifita, JA; Nicholson, GA; Blair, IP; Rouleau, GA; Esteban-Pérez, J; García-Redondo, A; Al-Chalabi, A; Consortium, Project MinE ALS Sequencing; Rogaeva, E; Zinman, L; Ostrow, LW; Maragakis, NJ; Rothstein, JD; Simmons, Z; Cooper-Knock, J; Brice, A; Goutman, SA; Feldman, EL; Gibson, SB; Taroni, F; Ratti, A; Gellera, C; Van Damme, P; Robberecht, W; Fratta, P; Sabatelli, M; Lunetta, C; Ludolph, AC; Andersen, PM; Weishaupt, JH; Camu, W; Trojanowski, JQ; Van Deerlin, VM; Brown RH, Jr; van den Berg, LH; Veldink, JH; Harms, MB; Glass, JD; Stone, DJ; Tienari, P; Silani, V; Chiò, A; Shaw, CE; Traynor, BJ; Landers, JE.

In: Neuron, Vol. 97, No. 6, 2018, p. 1268-1283.e6.

Research output: Contribution to journalArticle

Nicolas, A, Kenna, KP, Renton, AE, Ticozzi, N, Faghri, F, Chia, R, Dominov, JA, Kenna, BJ, Nalls, MA, Keagle, P, Rivera, AM, van Rheenen, W, Murphy, NA, van Vugt, JJFA, Geiger, JT, Van der Spek, RA, Pliner, HA, [No Value], S, Smith, BN, Marangi, G, Topp, SD, Abramzon, Y, Gkazi, AS, Eicher, JD, Kenna, A, Consortium, ITALSGEN, Mora, G, Calvo, A, Mazzini, L, Riva, N, Mandrioli, J, Caponnetto, C, Battistini, S, Volanti, P, La Bella, V, Conforti, FL, Borghero, G, Messina, S, Simone, IL, Trojsi, F, Salvi, F, Logullo, FO, D'Alfonso, S, Corrado, L, Capasso, M, Ferrucci, L, Consortium, GTFALSCGTAC, Moreno, CAM, Kamalakaran, S, Goldstein, DB, Consortium, ALSS, Gitler, AD, Harris, T, Myers, RM, Consortium, NYGCALS, Phatnani, H, Musunuri, RL, Evani, US, Abhyankar, A, Zody, MC, Foundation, AALS, Kaye, J, Finkbeiner, S, Wyman, SK, LeNail, A, Lima, L, Fraenkel, E, Svendsen, CN, Thompson, LM, Van Eyk, JE, Berry, JD, Miller, TM, Kolb, SJ, Cudkowicz, M, Baxi, E, ALS, CRI, Consortium, RDFTDCRT, Benatar, M, Taylor, JP, Rampersaud, E, Wu, G, Wuu, J, Consortium, SLAGEN, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, GP, Sorarù, G, Cereda, C, Consortium, FALS, Corcia, P, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, RW, Sidle, KC, Malaspina, A, Hardy, J, Singleton, AB, Johnson, JO, Arepalli, S, Sapp, PC, McKenna-Yasek, D, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, Baas, F, Ten Asbroek, ALMA, Muñoz-Blanco, JL, Hernandez, DG, Ding, J, Gibbs, JR, Scholz, SW, Floeter, MK, Campbell, RH, Landi, F, Bowser, R, Pulst, SM, Ravits, JM, MacGowan, DJL, Kirby, J, Pioro, EP, Pamphlett, R, Broach, J, Gerhard, G, Dunckley, TL, Brady, CB, Kowall, NW, Troncoso, JC, Le Ber, I, Mouzat, K, Lumbroso, S, Heiman-Patterson, TD, Kamel, F, Van Den Bosch, L, Baloh, RH, Strom, TM, Meitinger, T, Shatunov, A, Van Eijk, KR, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, McLaughlin, RL, Van Es, MA, Weber, M, Boylan, KB, Van Blitterswijk, M, Rademakers, R, Morrison, KE, Basak, AN, Mora, JS, Drory, VE, Shaw, PJ, Turner, MR, Talbot, K, Hardiman, O, Williams, KL, Fifita, JA, Nicholson, GA, Blair, IP, Rouleau, GA, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Consortium, PMALSS, Rogaeva, E, Zinman, L, Ostrow, LW, Maragakis, NJ, Rothstein, JD, Simmons, Z, Cooper-Knock, J, Brice, A, Goutman, SA, Feldman, EL, Gibson, SB, Taroni, F, Ratti, A, Gellera, C, Van Damme, P, Robberecht, W, Fratta, P, Sabatelli, M, Lunetta, C, Ludolph, AC, Andersen, PM, Weishaupt, JH, Camu, W, Trojanowski, JQ, Van Deerlin, VM, Brown RH, J, van den Berg, LH, Veldink, JH, Harms, MB, Glass, JD, Stone, DJ, Tienari, P, Silani, V, Chiò, A, Shaw, CE, Traynor, BJ & Landers, JE 2018, 'Genome-wide Analyses Identify KIF5A as a Novel ALS Gene', Neuron, vol. 97, no. 6, pp. 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027
Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R et al. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018;97(6):1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027
Nicolas, A ; Kenna, KP ; Renton, AE ; Ticozzi, N ; Faghri, F ; Chia, R ; Dominov, JA ; Kenna, BJ ; Nalls, MA ; Keagle, P ; Rivera, AM ; van Rheenen, W ; Murphy, NA ; van Vugt, JJFA ; Geiger, JT ; Van der Spek, RA ; Pliner, HA ; [No Value], Shankaracharya ; Smith, BN ; Marangi, G ; Topp, SD ; Abramzon, Y ; Gkazi, AS ; Eicher, JD ; Kenna, A ; Consortium, ITALSGEN ; Mora, G ; Calvo, A ; Mazzini, L ; Riva, N ; Mandrioli, J ; Caponnetto, C ; Battistini, S ; Volanti, P ; La Bella, V ; Conforti, FL ; Borghero, G ; Messina, S ; Simone, IL ; Trojsi, F ; Salvi, F ; Logullo, FO ; D'Alfonso, S ; Corrado, L ; Capasso, M ; Ferrucci, L ; Consortium, Genomic Translation for ALS Care (GTAC) ; Moreno, CAM ; Kamalakaran, S ; Goldstein, DB ; Consortium, ALS Sequencing ; Gitler, AD ; Harris, T ; Myers, RM ; Consortium, NYGC ALS ; Phatnani, H ; Musunuri, RL ; Evani, US ; Abhyankar, A ; Zody, MC ; Foundation, Answer ALS ; Kaye, J ; Finkbeiner, S ; Wyman, SK ; LeNail, A ; Lima, L ; Fraenkel, E ; Svendsen, CN ; Thompson, LM ; Van Eyk, JE ; Berry, JD ; Miller, TM ; Kolb, SJ ; Cudkowicz, M ; Baxi, E ; ALS, Clinical Research in ; Consortium, Related Disorders for Therapeutic Development (CReATe) ; Benatar, M ; Taylor, JP ; Rampersaud, E ; Wu, G ; Wuu, J ; Consortium, SLAGEN ; Lauria, G ; Verde, F ; Fogh, I ; Tiloca, C ; Comi, GP ; Sorarù, G ; Cereda, C ; Consortium, French ALS ; Corcia, P ; Laaksovirta, H ; Myllykangas, L ; Jansson, L ; Valori, M ; Ealing, J ; Hamdalla, H ; Rollinson, S ; Pickering-Brown, S ; Orrell, RW ; Sidle, KC ; Malaspina, A ; Hardy, J ; Singleton, AB ; Johnson, JO ; Arepalli, S ; Sapp, PC ; McKenna-Yasek, D ; Polak, M ; Asress, S ; Al-Sarraj, S ; King, A ; Troakes, C ; Vance, C ; de Belleroche, J ; Baas, F ; Ten Asbroek, ALMA ; Muñoz-Blanco, JL ; Hernandez, DG ; Ding, J ; Gibbs, JR ; Scholz, SW ; Floeter, MK ; Campbell, RH ; Landi, F ; Bowser, R ; Pulst, SM ; Ravits, JM ; MacGowan, DJL ; Kirby, J ; Pioro, EP ; Pamphlett, R ; Broach, J ; Gerhard, G ; Dunckley, TL ; Brady, CB ; Kowall, NW ; Troncoso, JC ; Le Ber, I ; Mouzat, K ; Lumbroso, S ; Heiman-Patterson, TD ; Kamel, F ; Van Den Bosch, L ; Baloh, RH ; Strom, TM ; Meitinger, T ; Shatunov, A ; Van Eijk, KR ; de Carvalho, M ; Kooyman, M ; Middelkoop, B ; Moisse, M ; McLaughlin, RL ; Van Es, MA ; Weber, M ; Boylan, KB ; Van Blitterswijk, M ; Rademakers, R ; Morrison, KE ; Basak, AN ; Mora, JS ; Drory, VE ; Shaw, PJ ; Turner, MR ; Talbot, K ; Hardiman, O ; Williams, KL ; Fifita, JA ; Nicholson, GA ; Blair, IP ; Rouleau, GA ; Esteban-Pérez, J ; García-Redondo, A ; Al-Chalabi, A ; Consortium, Project MinE ALS Sequencing ; Rogaeva, E ; Zinman, L ; Ostrow, LW ; Maragakis, NJ ; Rothstein, JD ; Simmons, Z ; Cooper-Knock, J ; Brice, A ; Goutman, SA ; Feldman, EL ; Gibson, SB ; Taroni, F ; Ratti, A ; Gellera, C ; Van Damme, P ; Robberecht, W ; Fratta, P ; Sabatelli, M ; Lunetta, C ; Ludolph, AC ; Andersen, PM ; Weishaupt, JH ; Camu, W ; Trojanowski, JQ ; Van Deerlin, VM ; Brown RH, Jr ; van den Berg, LH ; Veldink, JH ; Harms, MB ; Glass, JD ; Stone, DJ ; Tienari, P ; Silani, V ; Chiò, A ; Shaw, CE ; Traynor, BJ ; Landers, JE. / Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. In: Neuron. 2018 ; Vol. 97, No. 6. pp. 1268-1283.e6.
@article{c888693f4d7d447ba4812b75c29b87ad,
title = "Genome-wide Analyses Identify KIF5A as a Novel ALS Gene",
abstract = "To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS. {\circledC} 2018 Elsevier Inc.",
author = "A Nicolas and KP Kenna and AE Renton and N Ticozzi and F Faghri and R Chia and JA Dominov and BJ Kenna and MA Nalls and P Keagle and AM Rivera and {van Rheenen}, W and NA Murphy and {van Vugt}, JJFA and JT Geiger and {Van der Spek}, RA and HA Pliner and {[No Value]}, Shankaracharya and BN Smith and G Marangi and SD Topp and Y Abramzon and AS Gkazi and JD Eicher and A Kenna and ITALSGEN Consortium and G Mora and A Calvo and L Mazzini and N Riva and J Mandrioli and C Caponnetto and S Battistini and P Volanti and {La Bella}, V and FL Conforti and G Borghero and S Messina and IL Simone and F Trojsi and F Salvi and FO Logullo and S D'Alfonso and L Corrado and M Capasso and L Ferrucci and Consortium, {Genomic Translation for ALS Care (GTAC)} and CAM Moreno and S Kamalakaran and DB Goldstein and Consortium, {ALS Sequencing} and AD Gitler and T Harris and RM Myers and Consortium, {NYGC ALS} and H Phatnani and RL Musunuri and US Evani and A Abhyankar and MC Zody and Foundation, {Answer ALS} and J Kaye and S Finkbeiner and SK Wyman and A LeNail and L Lima and E Fraenkel and CN Svendsen and LM Thompson and {Van Eyk}, JE and JD Berry and TM Miller and SJ Kolb and M Cudkowicz and E Baxi and ALS, {Clinical Research in} and Consortium, {Related Disorders for Therapeutic Development (CReATe)} and M Benatar and JP Taylor and E Rampersaud and G Wu and J Wuu and SLAGEN Consortium and G Lauria and F Verde and I Fogh and C Tiloca and GP Comi and G Sorar{\`u} and C Cereda and Consortium, {French ALS} and P Corcia and H Laaksovirta and L Myllykangas and L Jansson and M Valori and J Ealing and H Hamdalla and S Rollinson and S Pickering-Brown and RW Orrell and KC Sidle and A Malaspina and J Hardy and AB Singleton and JO Johnson and S Arepalli and PC Sapp and D McKenna-Yasek and M Polak and S Asress and S Al-Sarraj and A King and C Troakes and C Vance and {de Belleroche}, J and F Baas and {Ten Asbroek}, ALMA and JL Mu{\~n}oz-Blanco and DG Hernandez and J Ding and JR Gibbs and SW Scholz and MK Floeter and RH Campbell and F Landi and R Bowser and SM Pulst and JM Ravits and DJL MacGowan and J Kirby and EP Pioro and R Pamphlett and J Broach and G Gerhard and TL Dunckley and CB Brady and NW Kowall and JC Troncoso and {Le Ber}, I and K Mouzat and S Lumbroso and TD Heiman-Patterson and F Kamel and {Van Den Bosch}, L and RH Baloh and TM Strom and T Meitinger and A Shatunov and {Van Eijk}, KR and {de Carvalho}, M and M Kooyman and B Middelkoop and M Moisse and RL McLaughlin and {Van Es}, MA and M Weber and KB Boylan and {Van Blitterswijk}, M and R Rademakers and KE Morrison and AN Basak and JS Mora and VE Drory and PJ Shaw and MR Turner and K Talbot and O Hardiman and KL Williams and JA Fifita and GA Nicholson and IP Blair and GA Rouleau and J Esteban-P{\'e}rez and A Garc{\'i}a-Redondo and A Al-Chalabi and Consortium, {Project MinE ALS Sequencing} and E Rogaeva and L Zinman and LW Ostrow and NJ Maragakis and JD Rothstein and Z Simmons and J Cooper-Knock and A Brice and SA Goutman and EL Feldman and SB Gibson and F Taroni and A Ratti and C Gellera and {Van Damme}, P and W Robberecht and P Fratta and M Sabatelli and C Lunetta and AC Ludolph and PM Andersen and JH Weishaupt and W Camu and JQ Trojanowski and {Van Deerlin}, VM and {Brown RH}, Jr and {van den Berg}, LH and JH Veldink and MB Harms and JD Glass and DJ Stone and P Tienari and V Silani and A Chi{\`o} and CE Shaw and BJ Traynor and JE Landers",
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TY - JOUR

T1 - Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

AU - Nicolas, A

AU - Kenna, KP

AU - Renton, AE

AU - Ticozzi, N

AU - Faghri, F

AU - Chia, R

AU - Dominov, JA

AU - Kenna, BJ

AU - Nalls, MA

AU - Keagle, P

AU - Rivera, AM

AU - van Rheenen, W

AU - Murphy, NA

AU - van Vugt, JJFA

AU - Geiger, JT

AU - Van der Spek, RA

AU - Pliner, HA

AU - [No Value], Shankaracharya

AU - Smith, BN

AU - Marangi, G

AU - Topp, SD

AU - Abramzon, Y

AU - Gkazi, AS

AU - Eicher, JD

AU - Kenna, A

AU - Consortium, ITALSGEN

AU - Mora, G

AU - Calvo, A

AU - Mazzini, L

AU - Riva, N

AU - Mandrioli, J

AU - Caponnetto, C

AU - Battistini, S

AU - Volanti, P

AU - La Bella, V

AU - Conforti, FL

AU - Borghero, G

AU - Messina, S

AU - Simone, IL

AU - Trojsi, F

AU - Salvi, F

AU - Logullo, FO

AU - D'Alfonso, S

AU - Corrado, L

AU - Capasso, M

AU - Ferrucci, L

AU - Consortium, Genomic Translation for ALS Care (GTAC)

AU - Moreno, CAM

AU - Kamalakaran, S

AU - Goldstein, DB

AU - Consortium, ALS Sequencing

AU - Gitler, AD

AU - Harris, T

AU - Myers, RM

AU - Consortium, NYGC ALS

AU - Phatnani, H

AU - Musunuri, RL

AU - Evani, US

AU - Abhyankar, A

AU - Zody, MC

AU - Foundation, Answer ALS

AU - Kaye, J

AU - Finkbeiner, S

AU - Wyman, SK

AU - LeNail, A

AU - Lima, L

AU - Fraenkel, E

AU - Svendsen, CN

AU - Thompson, LM

AU - Van Eyk, JE

AU - Berry, JD

AU - Miller, TM

AU - Kolb, SJ

AU - Cudkowicz, M

AU - Baxi, E

AU - ALS, Clinical Research in

AU - Consortium, Related Disorders for Therapeutic Development (CReATe)

AU - Benatar, M

AU - Taylor, JP

AU - Rampersaud, E

AU - Wu, G

AU - Wuu, J

AU - Consortium, SLAGEN

AU - Lauria, G

AU - Verde, F

AU - Fogh, I

AU - Tiloca, C

AU - Comi, GP

AU - Sorarù, G

AU - Cereda, C

AU - Consortium, French ALS

AU - Corcia, P

AU - Laaksovirta, H

AU - Myllykangas, L

AU - Jansson, L

AU - Valori, M

AU - Ealing, J

AU - Hamdalla, H

AU - Rollinson, S

AU - Pickering-Brown, S

AU - Orrell, RW

AU - Sidle, KC

AU - Malaspina, A

AU - Hardy, J

AU - Singleton, AB

AU - Johnson, JO

AU - Arepalli, S

AU - Sapp, PC

AU - McKenna-Yasek, D

AU - Polak, M

AU - Asress, S

AU - Al-Sarraj, S

AU - King, A

AU - Troakes, C

AU - Vance, C

AU - de Belleroche, J

AU - Baas, F

AU - Ten Asbroek, ALMA

AU - Muñoz-Blanco, JL

AU - Hernandez, DG

AU - Ding, J

AU - Gibbs, JR

AU - Scholz, SW

AU - Floeter, MK

AU - Campbell, RH

AU - Landi, F

AU - Bowser, R

AU - Pulst, SM

AU - Ravits, JM

AU - MacGowan, DJL

AU - Kirby, J

AU - Pioro, EP

AU - Pamphlett, R

AU - Broach, J

AU - Gerhard, G

AU - Dunckley, TL

AU - Brady, CB

AU - Kowall, NW

AU - Troncoso, JC

AU - Le Ber, I

AU - Mouzat, K

AU - Lumbroso, S

AU - Heiman-Patterson, TD

AU - Kamel, F

AU - Van Den Bosch, L

AU - Baloh, RH

AU - Strom, TM

AU - Meitinger, T

AU - Shatunov, A

AU - Van Eijk, KR

AU - de Carvalho, M

AU - Kooyman, M

AU - Middelkoop, B

AU - Moisse, M

AU - McLaughlin, RL

AU - Van Es, MA

AU - Weber, M

AU - Boylan, KB

AU - Van Blitterswijk, M

AU - Rademakers, R

AU - Morrison, KE

AU - Basak, AN

AU - Mora, JS

AU - Drory, VE

AU - Shaw, PJ

AU - Turner, MR

AU - Talbot, K

AU - Hardiman, O

AU - Williams, KL

AU - Fifita, JA

AU - Nicholson, GA

AU - Blair, IP

AU - Rouleau, GA

AU - Esteban-Pérez, J

AU - García-Redondo, A

AU - Al-Chalabi, A

AU - Consortium, Project MinE ALS Sequencing

AU - Rogaeva, E

AU - Zinman, L

AU - Ostrow, LW

AU - Maragakis, NJ

AU - Rothstein, JD

AU - Simmons, Z

AU - Cooper-Knock, J

AU - Brice, A

AU - Goutman, SA

AU - Feldman, EL

AU - Gibson, SB

AU - Taroni, F

AU - Ratti, A

AU - Gellera, C

AU - Van Damme, P

AU - Robberecht, W

AU - Fratta, P

AU - Sabatelli, M

AU - Lunetta, C

AU - Ludolph, AC

AU - Andersen, PM

AU - Weishaupt, JH

AU - Camu, W

AU - Trojanowski, JQ

AU - Van Deerlin, VM

AU - Brown RH, Jr

AU - van den Berg, LH

AU - Veldink, JH

AU - Harms, MB

AU - Glass, JD

AU - Stone, DJ

AU - Tienari, P

AU - Silani, V

AU - Chiò, A

AU - Shaw, CE

AU - Traynor, BJ

AU - Landers, JE

PY - 2018

Y1 - 2018

N2 - To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS. © 2018 Elsevier Inc.

AB - To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS. © 2018 Elsevier Inc.

U2 - 10.1016/j.neuron.2018.02.027

DO - 10.1016/j.neuron.2018.02.027

M3 - Article

VL - 97

SP - 1268-1283.e6

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 6

ER -